text:
On a New type of Tensor on Real Hypersurfaces in Non-Flat Complex Space Forms
Investigation of the Stereochemical-Dependent DNA and RNA Binding of Arginine-Based Nucleopeptides
Edge Detection Algorithm of a Symmetric Difference Kernel SAR Image Based on the GAN Network Model
MDPI — Symmetry
Lenci, E.
Trabocchi, A.
peptidomimetics
chiral pool
stereochemistry
Elena Lenci
Andrea Trabocchi
Open Access This article is
freely available
re-usable
Symmetry 2019, 11(4), 558; https://doi.org/10.3390/sym11040558
Occurrence of the d-Proline Chemotype in Enzyme Inhibitors
Elena Lenci 1,* and Andrea Trabocchi 1,2
Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, Sesto Fiorentino, 50019 Florence, Italy
Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy
Received: 29 March 2019 / Accepted: 17 April 2019 / Published: 18 April 2019
Natural and nonnatural amino acids represent important building blocks for the development of peptidomimetic scaffolds, especially for targeting proteolytic enzymes and for addressing protein–protein interactions. Among all the different amino acids derivatives, proline is particularly relevant in chemical biology and medicinal chemistry due to its secondary structure's inducing and stabilizing properties. Also, the pyrrolidine ring is a conformationally constrained template that can direct appendages into specific clefts of the enzyme binding site. Thus, many papers have appeared in the literature focusing on the use of proline and its derivatives as scaffolds for medicinal chemistry applications. In this review paper, an insight into the different biological outcomes of d-proline and l-proline in enzyme inhibitors is presented, especially when associated with matrix metalloprotease and metallo-β-lactamase enzymes.
drug discovery; amino acids; peptidomimetics; enzyme inhibitors; chiral pool; stereochemistry
More than 500 amino acids are present in nature. Although d-amino acids were long considered to have only a minor function compared to their enantiomers, many peptides that contain d-amino acids have been found in nature correlated to specific biological functions [1]. For example, bacterial cells wall peptidoglycans contain several d-amino acids, such as d-Asp, d-Asn, d-Glu, d-Gln, d-Ala, and d-Ser, that have been shown to give to bacteria the peculiar resistance to proteolytic digestion [2]. For the same reason, d-amino acids have been found in many antibiotics, such as bacitracin penicillin, actinomycin, and valinomycin. In humans, d-amino acids are often involved in pathophysiological processes [3] and can be used as disease markers [4]. Just to give some examples, d-serine is an important neuromodulator recognized by the N-methyl-d-aspartate (NMDA)-type glutamate receptors; its metabolism is altered in many neurodegenerative disorders [5,6]. Also, d-aspartate is implicated in the regulation of adult neurogenesis and in the development of endocrine functions, including hormones synthesis and spermatogenesis [7]. Generally, d-amino acids act antagonistically to l-amino acids by inhibiting the active site of biological targets [8]. This tendency is also demonstrated for synthetic amino acids. Just to give an example, l- and d-morpholine-3-carboxylic acid are able to modulate the conformational preferences [9,10] and the bioactivity of peptidomimetic compounds once inserted in their structure [11]. Specific enzymes, such as the amino acid racemase, the d-amino acid oxidase, and the peptidyl aminoacyl l-d-isomerase are present in our metabolism to convert the stereochemistry of specific amino acids in peptides or proteins [12,13].
Among all the different amino acids derivatives, proline is particularly relevant in chemical biology and medicinal chemistry due to the stabilizing properties and the conformational restriction of the pyrrolidine ring [14]. Proline-rich regions create peculiar secondary structures in proteins, such as β- and γ-turns and loops, which often play determining roles for protein–protein and protein–drug interactions [15]. Also, some proline-rich peptides have been shown to possess unique cell-penetrating properties [16]; others proved to have an antimicrobial activity by inhibiting protein synthesis [17] and to modulate the amyloid formation [18]. Finally, the alteration of hydroxyproline metabolism plays key roles in the many pathophysiological processes [19].
More than 100 drugs contain the l-proline chemotype in their structure. As representative examples, Figure 1 reports the structure of Telaprevir (1), a potent inhibitor of the Hepatitis C virus (HCV) that contains a proline derivative as an interacting motif able to address a binding pocket [20], and the structure of the antibiotic Clindamycin (2), useful for the treatment of a variety of different bacterial infections in which the proline is acting as a core scaffold to direct the substituents in the correct spatial orientation [21]. A substituted proline chemotype is also contained in compound 3, developed by Eli Lilly as a GLUK5 receptor antagonist [22], and in the structure of the antihypertensive drug Perindopril (4), where the proline is fused to a cyclohexane ring to further constrain the flexibility of the molecule [23].
Also, 21 entries of the drug bank database [24] contain the d-proline chemotype in their structure. In Figure 2 are represented the structures of the antibiotic Dalfopristin (5), which is used in combination with quinupristin to treat staphylococci infections [25], and of the antitumoral agent MDM2 inhibitor Idasanutlin (6) [26]. Two d-proline are present in Miridesap (7), a therapeutic agent able to enhance the degradation of amyloid P component [27], and in the structure of the antiarrhythmic Rotigaptide (8) [28].
d-proline plays key roles also in the pathophysiological processes of other organisms. Just to give some examples, adipokinetic neurohormones of cicadas differ only for the presence of l- or d-proline in their sequence [29]. Also, one of the mechanisms of the development of Chagas disease, caused by the infection of the protozoan parasite Trypanosoma cruzi [30], seems to be correlated to the overexpression of proline racemase. During the infection, T. cruzi secretes this enzyme, thus leading to the formation of several d-proline-rich peptides that showed a resistance against host proteolytic mechanisms [31]. Thus, proline racemase is a potential drug target against this parasite, and the development of its inhibitors can be used in the treatment of Chaga disease [32].
d-proline is also contained in Trapoxin B (9), Chlamydocin (10), and Apicidin B (11) (Figure 3), naturally occurring tetrapeptides that show a potent antiprotozoal activity by inhibiting histone deacetylase (HDAC), an enzyme that plays a key role in inducing or reversing gene transcription [33,34]. The importance of the d-proline ring in these compounds for the antiprotozoal activity has been clarified by Singh and coworkers [35]. In particular, while Apicidin B showed a 5-fold selectivity between the HDAC of the parasite and the HDAC of the liver of the chicken host, its synthetic analogue Apicidin C (12), where the (R)-proline ring is substituted with a (R)-piperidine ring, did not show any selectivity.
d- and l-proline have long attracted the interest of the medicinal chemistry community, and many papers are present in the literature focusing on the generation of proline derivatives as molecular scaffolds for the synthesis of peptidomimetics and enzyme inhibitors [36,37], also in a combinatorial chemistry [38] and Diversity-Oriented Synthesis perspective [39]. In this review paper, an insight into the different biological outcomes of d-proline and l-proline in enzyme inhibitors is presented, considering as case studies the matrix metalloprotease (MMP) and metallo-β-lactamase (MBL) enzymes.
2. d-Proline Derivatives as Metallo-β-Lactamase (MBL) Inhibitors
Antibiotic-resistant bacteria are becoming a serious threat of our century. Although many serine-dependent metallo-β-lactamases (SBL) are already currently used in combination with antibiotics, no clinically useful metallo-β-lactamase (MBL) inhibitors have been reported yet [40]. This is mainly due to the need of achieving a selective inhibition against MBL enzymes, while avoiding the inhibition of other structurally similar enzymes. Depending on the number of zinc ions in the catalytic sites, MBLs can be categorized into three subclasses (B1, B2, and B3). l-Captopril (13) (Figure 4a), developed in the 1970s as a human angiotensin-converting enzyme (ACE) inhibitor, is able also to block several MBLs. In particular, its diastereoisomer d-captopril (14) has proven to be more potent against MBLs, especially against those belonging to the B1 subclass (such as NDM-1, IMP-1, and BcII) because its conformation is more similar to the one adopted by the antibiotic hydrolysis product (Figure 4b). Also, considering that d-captopril is not particularly active against the ACE enzyme, this compound provides an interesting starting point for the development of selective therapeutic agents [41] because the B1 subclass is the most diffuse and clinically relevant [42,43].
In particular, numerous cases of antibiotic resistance have been associated to the activity of imipenemase (IMP-1) [44], one of the most potent MBL from B1 subclass. The binding mode of the two captopril stereoisomers to IMP-1 has been determined by crystallography (Figure 5) [45]. In both cases, the two Zn2+ ions in the active site are located at the end of the two β-sheets; one is chelated by three histidines, while the other one is coordinated by an aspartic acid, a histidine, and a cysteine [46,47]. In the complex with l-captopril, a decreased number of hydrogen bonds and weaker electrostatic interactions are found, which reflects its smaller inhibition.
Novel broad-spectrum inhibitors have been designed by using l-proline and d-proline as molecular scaffolds to direct the interacting groups in the correct spatial orientations. In particular, in order to determine the optimal distance between the thiol and the carboxylate functional groups, McGeary and coworkers synthesized compounds 15–20 (Figure 6), containing a different number of carbon atoms in the amide appendage [48]. The biological data showed that compounds 15 and 18, characterized by the shortest distance between these groups, are the most active, although only slightly more than the parent d- and l-captopril. Also, d-proline derivatives 18–20 were, in all cases, more potent than the corresponding l-proline derivatives, demonstrating the higher affinity of this conformation in coordinating both metal ions through the thiolate and the carboxylate functional groups.
The authors also synthesized l-proline and d-proline derivatives with two carboxylic acids (compounds 21–26, Figure 7). However, these compounds, including the succinic and glutaric anhydride derivatives, did not show any inhibition activity against IMP-1, thus revealing the importance of the thiol group for the binding affinity. The relevance of the carboxylate group linked to the proline ring was also demonstrated by derivatives 27–29, where the carboxylic group is spaced out by an ether group, that showed a significantly lower biological activity as compared to compounds 18–20.
3. d-Proline Derivatives as Matrix Metalloproteases (MMP) Inhibitors
Matrix metalloproteases (MMP) are a class of Zn2+-dependent proteases of the metzincin superfamily that are key players in the modeling of the extracellular matrix (ECM) [49]. The 23 members of the human MMP family are classified into six categories [50]. Many of them are involved in cancer development [51], as well as in inflammatory and cardiovascular diseases [52,53]. Unfortunately, the use of MMP inhibitors (MMPi) in the clinics has been stalled due to the development of side effects related to the nonselective inhibition of several metalloproteases [54]. Among the different types of MMPs, gelatinase A (MMP-2) and gelatinase B (MMP-9) have been shown to play a key role in the angiogenic switch, which is related to tumor cell invasiveness. However, MMP-2 is considered a better candidate target as compared than MMP-9, of which the inhibition can be even detrimental in advanced stages of cancer [55].
Several types of MMP-2 inhibitors have been developed during the last decades, most of them containing the hydroxamate functional group as an effective zinc binding element and at least one hydrophobic side chain effectively interacting with S1' and S2' pockets [56]. Early stage hydroxamates, such as batimastat (30), belong to the class of succinylate aminoacid hydroxamates, one of the most effective MMP binders, that unfortunately did not show any selectivity and failed the clinical trials [57]. Another class of effective MMPi are represented by α-sulfonyl-piperidine and α-sulfonyl-pyran hydroxamic acids, such as compound 31 in which the SO2 moiety is involved in several strong hydrogen bonds with amino acid residues from the active site cleft and in directing the hydrophobic substituent into the deep S1' cleft [58]. In this field, sulfonylated amino acid hydroxamates with general formula HONH-CO-CHR1-NR2-SO2R3, such as compound 32 (CGS27023A) developed by Novartis, have proven to be very effective, although toxicities related to arthralgia and myalgia were observed in clinical trials [59]. Other hydroxamate inhibitors containing a cyclic scaffold have been also reported, such as the ϒ-lactam hydroxamate 33 as in Figure 8, but these compounds were found to have only a sub-micromolar affinity for MMP-2.
In this context, proline has been taken into account as a molecular scaffold by several research groups, starting from the observation that collagen, one of the main components of the ECM, is composed by the repetition of the XaaYaaGly sequence, in which Xaa is often l-proline and Yaa is often trans-(2S,4R)-4-hydroxyproline [60,61]. Hannessian and coworkers developed a class of d-proline derivatives (compounds 34–42 as in Figure 9) possessing different appendages on position 3 of the pyrrolidine ring that can address the S1 pocket by an additional hydrogen bond donor [62]. However, these compounds did not show a satisfactory selectivity, as the p-methoxyphenyl moiety addressing the S1' pocket did not prove to be sufficient in discriminating between the two gelatinases.
In a complementary approach, the group of Taiwo and coworkers [63] reasoned to address the selectivity for the MMP-2 by introducing on position 4 of the pyrrolidine ring a panel of different functionalities, including amides, sulfonamides, and ureas. Also, different sulfonyl groups at the nitrogen atom of the proline core were attached in order to better study the influence of the aromatic group in addressing the S1' pocket. Fifty-six compounds (with general formula 43–46, Figure 10) were developed by this group starting from cis-4-hydroxy-d-proline and tested in vitro for the inhibition against collagenase-1 (MMP-1), gelatinase-A (MMP-2), stromelysin (MMP-3), matrilysin (MMP-7), and collagenase-3 (MMP-13). This class of compounds inhibits effectively MMP-2 and -13, with a good selectivity towards MMP-7. The inhibition of MMP-1 and MMP-3 proved to be more variable, depending on the functional group on position 4. However, while longer aliphatic substituents in the sulfonamide appendage resulted in an improvement of the selectivity for the MMP-2 enzyme, the insertion of different groups on position 4 did not show any remarkable effects.
The fact that functional groups at position 4 did not improve significantly the selectivity for MMP-2 versus MMP-9 was also assessed by our research group when we evaluated the inhibition profile of d-proline derivatives 47–57 (Figure 11) [64]. These compounds showed a general preference for the inhibition towards MMP-9 because the substituent and the stereochemistry at C-4, addressing the S2 pocket, were not sufficiently tuned to balance the strong interaction of the 3,4-dichlorophenyl moiety with the S1' pocket of MMP-9. This work also revealed that the R configuration at the C-4 stereocenter proved to give a better inhibition, as also confirmed in the paper by Xu and coworkers [65], where an array of α-sulfonyl γ-(glycinyl-amino)proline peptidomimetic derivatives with a cis-configuration at the proline scaffold showed a good selectivity for the MMP-2 enzyme over APN/CD13 (aminopeptidases) and HDACs.
For this reason, our research group tried to advance towards this direction by exploring the interaction of different N-arylsulfonyl moieties at the nitrogen atom within the S1' subsite, considering that the S1' pocket of MMP-9 showed a higher degree of hydrophobic nature with respect to that of MMP-2 [66]. Eight different d-proline derivatives were developed, possessing appendages with 1 to 3 rings (compounds 59–64 in Figure 12) and compared to the model compounds 57 and 58, synthesized as the unsubsituted reference compounds corresponding to those previously reported in the literature. The results of the in vitro screening against MMP-2 and MMP-9 purified enzymes, as well as of the cell-based assays, showed that compounds 63–64 with long hydrophobic chains showed a remarkable selectivity thanks to the existence of a long hydrophobic channel at the bottom of the S1' subsite in the MMP-2 catalytic cleft.
The importance of the long hydrophobic chain addressing the S1' pocket was also found to be important in achieving selectivity for other MMPs, as evinced by the work of Holl and coworkers [67]. In fact, d- and l-proline derivatives with general formula 65 and a long lipophilic tail (Figure 13) were found to be highly selective also for collagenase 3 (MMP-13), an important target not only for anticancer drug development but also in Alzheimer's disease [68]. Even in this case, it was evinced that the cis relative stereochemistry was found to be extremely important for the selectivity and the binding activity, as compounds derived from (2R,4R)-4-hydroxyproline were more potent than analogues with a (2S,4R)-4-hydroxyproline or a (2S)-proline scaffold. The best compound was found to be 66 possessing an n-pentyl moiety, as this compound showed a picomolar activity for MMP-13 and a great selectivity towards other MMPs as well as towards other Zn2+-dependent metalloproteases, such as ADAMs and meprins. Also, the [18F]-radiolabeled analogue was synthesized by this group and subjected to in vivo studies, revealing that this ligand possesses an excellent sereum stability and a relative rapid clearance in mice, demonstrating the valence of this ligand as a PET imaging tracer able to quantify the MMP-13 activity in a variety of in vivo pathological model systems.
Proline is one of the most relevant amino acids for chemical biology and medicinal chemistry applications due to the stabilizing properties and the conformational restriction of the pyrrolidine ring. Although for many years, researchers believed that d-amino acids have only a minor function as compared to their l-enantiomers, d-proline was shown to play a crucial role in many pathophysiological events. The d-Proline chemotype is contained in more than 20 approved or investigational drugs present in the drug bank database, as well as in the naturally occurring HDAC inhibitors of the Trapoxin family. d-Proline-rich peptides were shown to provide bacteria and parasites the peculiar resistance against host proteolytic mechanism. Also, the d-proline chemotype were shown to possess the right conformation to accommodate itself in the catalytic clefts of different metalloenzymes. Accordingly, d-proline derivatives have proven to efficiently inhibit the IMP-1 enzyme, belonging to the B1 subclass of metallo-β-lactamases (MBLs), one of the main targets responsible for antibiotic resistance, demonstrating the higher affinity of this conformation, as compared to the one adopted by l-proline derivatives, in coordinating both Zn2+ ions through the thiolate and the carboxylate functional groups. Also, d-proline derivatives, possessing different appendages on position 3/4 of the pyrrolidine ring and different N-arylsulfonyl moieties, have been designed to selectively inhibit some matrix metalloprotease (MMP) enzymes, including gelatinase A (MMP-2), a validated molecular target in cancer drug discovery. Even in this case, the relative cis-configuration of the two hydrophobic groups linked to the pyrrolidine scaffold was found to be extremely important for selectivity and binding activity, as compounds derived from (2R,4R)-4-hydroxy-d-proline were more potent than analogues with a (2S,4R)-4-hydroxy-d-proline or a l-proline scaffold. One of the main limitations of using d-proline for the development of enzyme inhibitors is related to the cis/trans isomerization process. As for l-proline, the small energy difference between the two conformations results in a high probability of finding both the cis and trans isomers in solution even at room temperature. This isomerization plays a key role in affecting the geometry and, consequently, the biological output of the peptides or of the peptidomimetic compounds. However, this limitation can be controlled intentionally by replacing d-proline with suitable analogues in which the rotational flexibility is reduced by bulky substituents, heteroatoms, or different sizes of the ring. Thus, the potential of d-proline as a conformationally restricted scaffold for the development of enzyme inhibitors has drawn considerable interest in the organic and medicinal chemistry community, and there is still much room left for the generation of novel small molecules for a drug discovery purpose around this scaffold.
E.L. and A.T. conceived and wrote the paper.
This research was funded by MIUR (PRIN2015, cod. 20157WW5EH), Fondazione CR Firenze (cod. 2017.0721), CNR roadmap europea ESFRI: CISPIM, and the University of Florence.
Genchi, G. An overview on D-amino acids. Amino Acids 2017, 49, 1521–1533. [Google Scholar] [CrossRef] [PubMed]
Veiga, P.; Piquet, S.; Maisons, A.; Furlan, S.; Courtin, P.; Chapot-Chartier, M.P.; Kulakauskas, S. Identification of an essential gene responsible for d-Asp incorporation in the Lactococcus lactis peptidoglycan crossbridge. Mol. Microbiol. 2006, 62, 1713–1724. [Google Scholar] [CrossRef] [PubMed]
Hamase, K.; Morikawa, A.; Zaitsu, K. D-amino acids in mammals and their diagnostic value. J. Chromatogr. B Anal. Technol. Biomed Life Sci. 2002, 781, 73–91. [Google Scholar] [CrossRef]
Hamase, K. Sensitive two-dimensional determination of small amounts of D-amino acids in mammals and the study on their functions. Chem. Pharm. Bull. 2007, 55, 503–510. [Google Scholar] [CrossRef] [PubMed]
Fuchs, S.A.; Berger, R.; Klomp, L.W.; de Koning, T.J. D-amino acids in the central nervous system in health and disease. Mol. Genet. Metab. 2005, 85, 168–180. [Google Scholar] [CrossRef]
Bauer, D.; Hamacher, K.; Bröer, S.; Pauleit, D.; Palm, C.; Zilles, K.; Coenen, H.; Langen, K.J. Preferred stereoselective brain uptake of d-serine-a modulator of glutamatergic neurotransmission. Nucl. Med. Biol. 2005, 32, 793–797. [Google Scholar] [CrossRef] [PubMed]
D'Aniello, A. D-aspartic acid: An endogenous amino acid with an important neuroendocrine role. Brain Res. Rev. 2007, 53, 215–234. [Google Scholar] [CrossRef]
Friedman, M.; Levin, C.E. Nutritional and medicinal aspects of D-amino acids. Amino Acids 2012, 42, 1553–1582. [Google Scholar] [CrossRef]
Sladojevich, F.; Guarna, A.; Trabocchi, A. Evaluation of stereochemically dense morpholine-based scaffolds as proline surrogates in β-turn peptides. Org. Biomol. Chem. 2010, 7, 916–924. [Google Scholar] [CrossRef]
Sladojevich, F.; Trabocchi, A.; Guarna, A. Configurationally-driven folding of model tetrapeptides containing l- or d-morpholine-3-carboxylic acids as β-turn nucleators. Chirality 2009, 21, 584–594. [Google Scholar]
Cini, N.; Trabocchi, A.; Menchi, G.; Bottoncetti, A.; Raspanti, S.; Pupi, A.; Guarna, A. Morpholine-based RGD-cyclopentapeptides as αvβ3/αvβ5 integrin ligands: Role of configuration towards receptor binding affinity. Biorg. Med. Chem. 2009, 17, 1542–1549. [Google Scholar] [CrossRef]
Yoshimura, T.; Esak, N. Amino acid racemases: Functions and mechanisms. J. Biosci. Bioeng. 2003, 96, 103–109. [Google Scholar] [CrossRef]
Ollivaux, C.; Soyez, D.; Toullec, J.Y. Biogenesis of d-amino acid containing peptides/proteins: Where, when and how? J. Pept. Sci. 2014, 20, 595–612. [Google Scholar] [CrossRef]
Mauger, A.B. Naturally Occurring Proline Analogues. J. Nat. Prod. 1996, 59, 1205–1211. [Google Scholar] [CrossRef]
Newberry, R.W.; Raines, R.T. The n → π * interaction. Acc. Chem. Res. 2017, 50, 1838–1846. [Google Scholar] [CrossRef]
Sanchez-Navarro, M.; Teixido, M.; Giralt, E. Jumping hurdles: Peptides able to overcome biological barriers. Acc. Chem. Res. 2017, 50, 1847–1854. [Google Scholar] [CrossRef]
Graf, M.; Mardirossian, M.; Nguyen, F.; Seefeldt, A.C.; Guichard, G.; Scocchi, M.; Innis, C.A.; Wilson, D.N. Proline-rich antimicrobial peptides targeting protein synthesis. Nat. Prod. Rep. 2017, 34, 702–711. [Google Scholar] [CrossRef]
Kraus, A. Proline and lysine residues provide modulatory switches in amyloid formation: Insights from prion protein. Prion 2016, 10, 57–62. [Google Scholar] [CrossRef][Green Version]
Srivastava, A.K.; Khare, P.; Nagar, H.K.; Raghuwanshi, N.; Srivastava, R. Hydroxyproline: A potential biochemical marker and its role in the pathogenesis of different diseases. Curr. Protein. Pept. Sci. 2016, 17, 596–602. [Google Scholar] [CrossRef]
Dienstag, J.L. Antiviral Drugs against Hepatitis Viruses. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th ed.; Bennett, J.E., Dolin, R., Blaser, M.J., Eds.; Elsevier: Philadelphia, PA, USA, 2015; Volume 1, pp. 563–575. [Google Scholar]
Smieja, M. Current indications for the use of clindamycin: A critical review. Can. J. Infect. Dis. 1998, 9, 22–28. [Google Scholar] [CrossRef]
Weiss, B.; Alt, A.; Ogden, A.M.; Gates, M.; Dieckman, D.K.; Clemens-Smith, A.; Ho, K.H.; Jarvie, K.; Rizkalla, G.; Wright, R.A.; et al. Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo. J. Pharm. Exp. 2006, 318, 772–781. [Google Scholar] [CrossRef] [PubMed]
Ng, K.; Butlin, M.; Avolio, A.P. Persistent effect of early, brief angiotensin-converting enzyme inhibition on segmental pressure dependency of aortic stiffness in spontaneously hypertensive rats. J. Hypertens. 2012, 30, 1782–1790. [Google Scholar] [CrossRef] [PubMed]
Drug Bank. Available online: https://www.drugbank.ca (accessed on 20 February 2019).
Allington, D.R.; Rivey, M.P. Quinupristin/dalfopristin: A therapeutic review. Clin. Ther. 2001, 23, 24–44. [Google Scholar] [CrossRef]
Seipel, K.; Marques, M.A.T.; Sidler, C.; Mueller, B.U.; Pabst, T. The Cellular p53 Inhibitor MDM2 and the Growth Factor Receptor FLT3 as Biomarkers for Treatment Responses to the MDM2-Inhibitor Idasanutlin and the MEK1 Inhibitor Cobimetinib in Acute Myeloid Leukemia. Cancers 2018, 10, 170. [Google Scholar] [CrossRef]
Gillmore, J.D.; Tennent, G.A.; Hutchinson, W.L.; Gallimore, J.R.; Lachmann, H.J.; Goodman, H.J.B.; Offer, M.; Millar, D.J.; Petrie, A.; Hawkins, P.N.; et al. Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis. Br. J. Haematol. 2010, 148, 760–767. [Google Scholar] [CrossRef][Green Version]
Pedersen, C.M.; Venkatasubramanian, S.; Vase, H.; Hyldebrandt, J.A.; Contractor, H.; Schmidt, M.R.; Bøtker, H.E.; Cruden, N.L.; Newby, D.E.; Kharbanda, R.K.; et al. Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury. Br. J. Clin. Pharmacol. 2016, 81, 1037–1045. [Google Scholar] [CrossRef][Green Version]
König, S.; Marco, H.; Gäde, G. The hypertrehalosemic neuropeptides of cicadas are structural isomers—evidence by ion mobility mass spectrometry. Anal. Bioanal. Chem. 2017, 409, 6415–6420. [Google Scholar] [CrossRef] [PubMed]
Reina-San-Martin, B.; Degrave, W.; Rougeot, C.; Cosson, A.; Chamond, N.; Cordeiro-Da-Silva, A.; Arala-Chaves, M.; Coutinho, A.; Minoprio, P. A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase. Nat. Med. 2000, 6, 890–897. [Google Scholar] [CrossRef] [PubMed]
Coatnoan, N.; Berneman, A.; Chamond, N.; Minoprio, P. Proline racemases: Insights into Trypanosoma cruzi peptides containing D-proline. Mem. Inst. Oswaldo Cruz 2009, 104, 295–300. [Google Scholar] [CrossRef]
Chamond, N.; Goytia, M.; Coatnoan, N.; Barale, J.C.; Cosson, A.; Degrave, W.M.; Minoprio, P. Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity. Mol. Microbiol. 2005, 58, 46–60. [Google Scholar] [CrossRef][Green Version]
Islam, M.S.; Bhuiyan, M.P.I.; Islam, M.N.; Nsiama, T.K.; Oishi, N.; Kato, T.; Nishino, N.; Ito, A.; Yoshida, M. Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition. Amino Acids 2012, 42, 2103–2110. [Google Scholar] [CrossRef]
Yoshida, M.; Matsuayama, A.; Komatsu, Y.; Nishino, N. From discovery to the coming generation of histone deacetylase inhibitors. Curr. Med. Chem. 2003, 10, 2351–2358. [Google Scholar] [CrossRef] [PubMed]
Singh, S.B.; Zink, D.L.; Liesch, J.M.; Dombrowski, A.W.; Darkin-Rattray, S.J.; Schmatz, D.M.; Goet, M.A. Structure, Histone Deacetylase, and Antiprotozoal Activities of Apicidins B and C, Congeners of Apicidin with Proline and Valine Substitutions. Org. Lett. 2001, 3, 2815–2818. [Google Scholar] [CrossRef] [PubMed]
Trabocchi, A.; Guarna, A. Cyclic α-Amino Acids as Proline Mimetics. In Peptidomimetics in Organic and Medicinal Chemistry: The Art of Transforming Peptides in Drugs, 1st ed.; Trabocchi, A., Guarna, A., Eds.; John Wiley and Sons, Ltd: Chichester, UK, 2014; pp. 165–190. [Google Scholar]
Luppi, G.; Lanci, D.; Trigari, V.; Garavelli, M.; Garelli, A.; Tomasini, A. Development and conformational analysis of a pseudoproline-containing turn mimic. J. Org. Chem. 2003, 68, 1982–1993. [Google Scholar] [CrossRef] [PubMed]
Kern, D.; Schutkowski, M.; Drakenberg, T. cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the 'unpuckered' proline. J. Am. Chem. Soc. 1997, 119, 8403–8408. [Google Scholar] [CrossRef]
Beausoleil, E.; L'Archevêque, B.; Bélec, L.; Atfani, M.; Lubell, W.D. 5-tert-Butylproline. J. Org. Chem. 1996, 61, 9447–9454. [Google Scholar] [CrossRef]
Cornaglia, G.; Giamarellou, H.; Rossolini, G.M. Metallo-β-lactamases: A last frontier for -lactams? Lancet Infect. Dis. 2011, 11, 381–393. [Google Scholar] [CrossRef]
Heinz, U.; Bauer, R.; Wommer, S.; Meyer-Klaucke, W.; Papamichaels, C.; Bateson, J.; Adolph, H.W. Coordination Geometries of Metal Ions in d- or l-Captopril-inhibited Metallo-β-lactamases. J. Biol. Chem. 2003, 278, 20659–20666. [Google Scholar] [CrossRef]
Karsisiotis, A.I.; Damblon, C.F.; Roberts, G.C.K. A Variety of Roles for versatile zinc in Metallo-β-lactamases. Metallomics 2014, 6, 1181–1197. [Google Scholar] [CrossRef]
Brem, J.; van Berkel, S.S.; Zollman, D.; Lee, S.Y.; Gileadi, O.; McHugh, P.J.; Walsh, T.R.; McDonough, M.A.; Schofield, C.J. Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers. Antimicrob. Agents Chemother. 2015, 60, 142–150. [Google Scholar] [CrossRef][Green Version]
Faridoon; Hussein, W.M.; Vella, P.; Nazar, U.I.; Ollis, D.L.; Schenk, G.; McGeary, R.P. 3-Mercapto-1,2,4-triazoles and N-acylated Thiosemicarbazides as Metallo-β-lactamase Inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 380–386. [Google Scholar] [CrossRef]
Page, M.I.; Badarau, A. The Mechanism of Catalysis by Metallo-β-Lactamases. Bioinorg. Chem. Appl. 2008, 1–14. [Google Scholar] [CrossRef]
Bebrone, C. Metallo-β-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. Biochem. Pharm. 2007, 74, 1686–1701. [Google Scholar] [CrossRef]
Goto, M.; Takahashi, T.; Yamashita, F.; Koreeda, A.; Mori, H.; Ohta, M.; Arakawa, Y. Inhibition of the Metallo-β-lactamase Produced from Serratia marcescens by Thiol Compounds. Biol. Pharm. Bull. 1997, 20, 1136–1140. [Google Scholar] [CrossRef]
Yusof, Y.; Tan, D.T.C.; Arjomandi, O.K.; Schenk, G.; McGeary, R.P. Captopril Analogues as Metallo-β-lactamase Inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 1589–1593. [Google Scholar] [CrossRef]
Cathcart, J.; Pulkoski-Gross, A.; Cao, J. Targeting matrix metalloproteinases in cancer: Bringing new life to old ideas. Genes Dis. 2015, 2, 26–34. [Google Scholar] [CrossRef][Green Version]
Visse, R.; Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ. Res. 2003, 92, 827–839. [Google Scholar] [CrossRef]
Rundhaug, J.E. Matrix metalloproteinases and angiogenesis. J. Cell. Mol. Med. 2005, 9, 267–285. [Google Scholar] [CrossRef]
Vihinen, P.; Ala-aho, R.; Kahari, V.M. Matrix metalloproteinases as therapeutic targets in cancer. Curr. Cancer Drug Targets 2005, 5, 203–220. [Google Scholar] [CrossRef]
Fingleton, B. Targeting monocyte chemoattractant protein-1 signalling in disease. Expert Opin. Tar. 2003, 7, 385–390. [Google Scholar] [CrossRef]
Coussens, L.M.; Fingleton, B.; Matrisian, L.M. Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations. Science 2002, 295, 2387–2392. [Google Scholar] [CrossRef] [PubMed]
Vandenbroucke, R.E.; Libert, C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat. Rev. Drug Discov. 2014, 13, 904–927. [Google Scholar] [CrossRef]
Li, N.G.; Shi, Z.H.; Tang, Y.P.; Duan, J.A. Selective matrix metalloproteinase inhibitors for cancer. Curr. Med. Chem. 2009, 16, 3805–3827. [Google Scholar] [CrossRef]
Beattie, G.J.; Young, H.A.; Smyth, J.F. Phase I study of intra-peritoneal metalloproteinase inhibitor BB-94 in patients with malignant ascites. Ann. Oncol. 1994, 5, 72a. [Google Scholar]
Rothenberg, M.L.; Nelson, A.R.; Hande, K.R. New Drugs on the Horizon: Matrix Metalloproteinase Inhibitors. Oncologist 1998, 3, 271–274. [Google Scholar] [CrossRef] [PubMed]
Levitt, N.C.; Eskens, F.A.; O'Byrne, K.J.; Propper, D.J.; Denis, L.J.; Owen, S.J.; Choi, L.; Foekens, J.A.; Wilner, S.; Wood, J.M.; et al. A phase one pharmacokinetic study of CGS27023A, a matrix metalloproteinase inhibitor. Proc. Am. Soc. Clin. Oncol. 1998, 17, 213a. [Google Scholar]
Jenkins, C.L.; McCloskey, A.I.; Guzei, I.A.; Eberhardt, E.S.; Raines, R.T. O-acylation of hydroxyproline residues: Effect on peptide-bond isomerization and collagen stability. Biopolymers 2005, 80, 1–8. [Google Scholar] [CrossRef] [PubMed]
Vitagliano, L.; Berisio, R.; Mazzarella, L.; Zagari, A. Structural bases of collagen stabilization induced by proline hydroxylation. Biopolymers 2001, 58, 459–464. [Google Scholar] [CrossRef]
Hanessian, S.; MacKay, D.B.; Moitessier, N. Design and Synthesis of Matrix Metalloproteinase Inhibitors Guided by Molecular Modeling. Picking the S1 Pocket Using Conformationally Constrained Inhibitors. J. Med. Chem. 2001, 44, 3074–3082. [Google Scholar] [CrossRef]
Natchus, M.G.; Bookland, R.G.; De, B.; Almstead, N.G.; Pikul, S.; Janusz, M.J.; Heitmeyer, S.A.; Hookfin, E.B.; Hsieh, L.C.; Dowty, M.E.; et al. Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines. J. Med. Chem. 2000, 43, 4948–4963. [Google Scholar] [CrossRef] [PubMed]
Bianchini, F.; Calugi, C.; Ruzzolini, J.; Menchi, G.; Calorini, L.; Guarna, A.; Trabocchi, A. A study of a D-proline peptidomimetic inhibitor of melanoma and endothelial cell invasion through activity towards MMP-2 and MMP-9. Med. Chem. Comm. 2015, 6, 277–282. [Google Scholar] [CrossRef]
Zhang, J.; Li, X.; Jiang, Y.; Feng, J.; Li, X.; Zhang, Y.; Xu, W. Design, synthesis and preliminary evaluation of α-sulfonyl γ-(glycinyl-amino)proline peptidomimetics as matrix metalloproteinase inhibitors. Bioorg. Med. Chem. 2014, 22, 3055–3064. [Google Scholar] [CrossRef] [PubMed]
Lenci, E.; Innocenti, R.; Di Francescantonio, T.; Menchi, G.; Bianchini, F.; Contini, A.; Trabocchi, A. Identification of highly potent and selective MMP2 inhibitors addressing the S1' subsite with d-proline-based compounds. Bioorg. Med. Chem. 2019, 27, 1891–1902. [Google Scholar] [CrossRef] [PubMed]
Kalinin, D.V.; Wagner, S.; Riemann, B.; Hermann, S.; Schmidt, F.; Becker-Pauly, C.; Rose-John, S.; Schäfers, M.; Holl, R. Novel Potent Proline-Based Metalloproteinase Inhibitors: Design, (Radio)Synthesis, and First in Vivo Evaluation as Radiotracers for Positron Emission Tomography. J. Med. Chem. 2016, 59, 9541–9559. [Google Scholar] [CrossRef]
Paumier, J.M.; Thinakaran, G. Matrix metalloproteinase 13, a new target for therapy in Alzheimer's disease. Genes Dis. 2019, 16, 1–2. [Google Scholar] [CrossRef] [PubMed]
Figure 1. The approved or investigational drugs containing the l-proline chemotype.
Figure 2. The approved or investigational drugs containing the d-proline chemotype.
Figure 3. The naturally occurring cyclic tetrapeptides containing d-proline (9–11) and the structurally related Apicidin C (12).
Figure 4. (a) l- and d-captopril and their inhibition activities towards different metallo-β-lactamase (MBLs) of the B1 subclass: (b) The hydrolyzed penicillin product shows a higher structural similarity to d-captopril as compared to l-captopril.
Figure 5. (a) The selected amino acids of the IMP-1 catalytic site interacting with l-captopril (PDB code: 4C1F) and (b) with d-captopril (PDB code: 4C1G). Zinc ions are shown as black spheres, amino acid residues are shown in light blue, and captopril molecules are shown in fuchsia.
Figure 6. l- and d-proline derivatives 15–20 and their inhibition activity against IMP-1.
Figure 8. Different MMPi developed in the last twenty years.
Figure 9. d-proline derivatives 35–42 developed by Hannessian and coworkers, their binding activity for MMP-2, and their selectivity between the two gelatinases (MMP-9/MMP-2).
Figure 10. The general formula of d-proline derivatives 43–46 developed by Taiwo and coworkers, their binding activity for MMP-2, and their selectivity between other MMPs (MMP-1, MMP-3, MMP-7, and MMP-13).
Figure 11. d-proline derivatives 47–56 developed by Trabocchi and coworkers, their binding activity for MMP-2, and their selectivity between the two gelatinases (MMP-9/MMP-2).
Figure 13. d-proline derivatives with general formula 65 developed by Holl and coworkers, their binding activity for MMP-2 and MMP-13, and their selectivity towards MMP-9 and MMP-8: The structure of the most potent and selective compound 66 and of its radiolabeled analogue.
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Symmetry EISSN 2073-8994 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert


Today I'm going to show you a recipe I'm really proud of: king-size kimchi-filled dumplings, or kimchi-wangmandu in Korean. Mandu is the Korean word for dumplings, and recently I showed you how to make your own dumpling skins (mandu-pi in Korean). You can use them for this recipe. I showed you how to make them large, because we're going to make king-size mandu today: big and substantial. Two or three king mandu should be enough for one meal. If you don't make your own skins you can buy them in a Korean grocery store.
These mandu are made with fermented kimchi, so they have a serious savory kick, and I also use ground beef, ginger, garlic, and chopped onion, noodles, and tofu which make them full of flavor and juicy.
Kimchi mandu are authentically Korean and really delicious, and I worked and reworked this recipe's ratio and technique until I was fully satisfied with the end result. I ate a lot of mandu! But it was worth it in the end, because these are so good. I'm still eating them!
What you need to do is make many of them at a time – 16 in this recipe – and freeze the leftovers for later use. Then they're always on hand and you can have mandu any time you want. If you like this recipe, also check out my other mandu recipes: fluffy steamed pork buns (Jjinppang-mandu) and Korean dumplings (mandu), which don't use kimchi.
I hope you make some delicious mandu for your family and friends and have a lot of fun making and eating them. I guarantee everyone will love these, so be sure to make big batches of kimchi king mandu!
Take your mandu wrappers out of the freezer. They can thaw out while we prepare the fillings.
Place the beef, garlic, and ginger into a bowl. Use a wooden spoon to mix with 2 teaspoons soy sauce, 1 tablespoon sugar, 2 teaspoons sesame oil, and ½ ts ground black pepper. You can use a food processor if you want to.
Heat up a skillet over medium high heat and add 1 teaspoon vegetable oil. Stir fry the meat mixture until the meat is no longer pink.
Transfer to a large mixing bowl and be sure to include the juices from the cooked meat.
Bring about 7 to 8 cups of water in a pot to a boil over medium high heat. Add the dangmyeon (aka sweet potato starch noodles) to the boiling water. Cover and cook for 7 to 8 minutes.
Take a sample of the noodles to see if they're cooked thoroughly. They should be soft with no firm bits in them at all. Strain and rinse under running cold water. Drain. Chop into small pieces. Add to the mixing bowl.
Add the minced onion, the chives, and kimchi to the mixing bowl.
Squeeze the tofu slightly by hand to remove excess water and add it to the mixing bowl.
Put a wrapper on your palm and add 2 or 3 spoons of filling to the center.
Loosely fold it in half vertically. Pinch the bottom on the fold to seal it.
Push the right side in a little bit, so the wrapper folds in on itself slightly.
Pinch that fold to make a pleat.
Do the same on the left side and alternate sides all the way up until the mandu is sealed.
Pinch or wrap the end to seal it.
Repeat until you've made mandu from all your fillings.
Set the mandu on a tray lined with plastic wrap so they aren't touching each other.
Put into the freezer for 8 hours or so, until they are all frozen.
Gently put them into a plastic bag or airtight container and put them back into the freezer.
Boil water in a steamer. Line the steamer rack or basket with a parchment paper.
Place some mandu in the steamer basket, but be sure to make room between the mandu because they will expand slightly when cooked. Cover and steam for 15 minutes.
Remove and serve with dipping sauce.
Heat up a non-stick pan over medium high heat. Add 2 tablespoons vegetable oil and swirl to spread the oil evenly.
Add some mandu and cook over medium heat, rotating them so each side gets golden-brown.
Lower the heat to low and cover. Cook for a few more minutes.
Combine 2 tablespoons of soy sauce, 1 tablespoon of white vinegar, ¼ cup chunks of onion, 1 chopped green chili pepper (or jalapeño) in a bowl.
Mix well. Optionally, if you like it sweet, add 1 teaspoon sugar.
Posted on Tuesday, September 9th, 2014 at 6:01 pm. Last updated on May 27, 2016.
Posted July 9th, 2018 at 8:52 pm | Log in to reply.
Would like to check with your if the pork/beef did not pre-cooked.
it could be keep at freezer for how long time?
Need your advise, i have go thru alot comment but did not see anyone asking about this..
Posted November 12th, 2017 at 4:14 am | Log in to reply.
It is a real pleasure to watch this video clips.
There are some questions where i hope you can help. It will be appreciated.
4. Can we immediately steam or fry the dumpling from the freezer or do they need to be taken out to get it soften before cooking.
Posted December 15th, 2017 at 9:08 pm | Log in to reply.
1. I just made a smaller version of the Kimchi Mandu using store-bought mandu (gyoza) skin.. if you are planning to make the skin yourself, based on my experience before, you can layer the skin on top of each other, but make sure you sprinkle some flour in between the layers so that they don't stick to each other.
2. If you are going to use it for tomorrow party and if you are making fresh mandu, you would need to put the dumplings in a single layer , but you don't have to freeze it. Just put it neatly on the non freezer fridge.
4. If you want to boil them, you don't have to thaw them first. But just make sure that your water has boiled properly.
However, if you want fried dumpling, i think it is better if you thaw them for a while, otherwise the skin would crack and the fillings will leak out.
There is another method that i like to use. I would pan fry the mandu with little oil, then after the bottom part of mandu has browned, i would pour some water (be careful as the water may splash) and cover the pan. The mandu would be cooked by the steam from the water.
Hope it helps, and happy cooking!
Posted December 15th, 2017 at 9:10 pm | Log in to reply.
Posted December 16th, 2017 at 9:58 pm | Log in to reply.
Posted July 2nd, 2017 at 9:09 pm | Log in to reply.
Thanks so much for sharing your cooking techniques online. I never prepared Korean food before learning from your Youtube videos, but for several months now, I prepare many of your recipes, mostly for breakfast. My favorite has to be pajeong, but I love making mandu also and doenjang jigae…well, on and on. Just tried the wangmandu this morning and we have several chilling in the freezer to enjoy later in the week.
Quick story: About 18 years ago my 15 year old son and I were stopped over on a plane flight in Seoul for about 8 hours. We'd never been to Korea before and it was barely dawn, so we, and two friends, walked from the budget hotel where we were staying out into a small, partly residential , partly commercial, neighborhood, looking for a place to find an early breakfast. Everything was closed up and steel shutters pulled down in front of the businesses. There was a shop that had dried fish displayed in a window and as we stood there, a friendly man came up and asked us what we wanted. When we explained, he knocked on the door and an old woman opened the shop for us and prepared the fish in some broth cooked on a gas burner, and served us that with gim and rice and kimchi. It was my first ever Korean food. We left Korea that afternoon, continuing our flight. Over the years I used to think back on that experience and realize that although I'd spent some time cooking western food professionally, and lived in cities like San Francisco and eaten in some very nice places, that breakfast in Seoul was the best breakfast I had ever eaten. Finally, a few months ago, I decided to research Korean food and found you on Youtube. Your recipes have brought a lot of pleasure to me and my family. Below is this morning's breakfast, if I can make the image work, on a very messy cutting board. Wangmandu, soft rice, gim, pickled garlic and steamed egg.
Posted June 18th, 2017 at 6:51 am | Log in to reply.
I made these for dinner tonight and they turned out great! I followed your recipe for mandu-pi, but mine turned out a lot smaller than yours. It's really difficult to roll the dough in a perfect circle, but you make it look so easy! I might buy pre-made mandu-pi next time I make these. Thanks for the great recipe!
Posted June 3rd, 2017 at 5:11 pm | Log in to reply.
how to use freeze mandu?!
Posted October 20th, 2016 at 9:28 am | Log in to reply.
This was an amazing dinner last week. We saved some to take for simple lunches at work.
Posted October 21st, 2016 at 8:09 am | Log in to reply.
Yes, it looks amazing! Huge dumplings filled with all delicious stuff means generosity! You made great wangmandu!
Posted August 21st, 2016 at 9:24 am | Log in to reply.
how many grams in 1 pound of ground pork? 450g or 500g?
Posted August 21st, 2016 at 11:41 am | Log in to reply.
1 pound pork is 453 grams.
Posted November 4th, 2016 at 11:01 pm | Log in to reply.
Posted June 19th, 2016 at 10:55 am | Log in to reply.
Posted March 25th, 2016 at 7:22 am | Log in to reply.
Thank you for excellent recipe.
This recipe was originally posted on September 9, 2014 at 6:01 pm by Maangchi. It was last updated on May 27, 2016.
The video was watched 2,184,723 times on YouTube & has 30,627 likes!


text:
Biografia
Figlio di Cesare Battisti e Ernesta Bittanti, a 16 anni andò alla Scuola di Caserta dove diventò sottotenente degli Alpini. In seguito venne mandato sul fronte al Passo del Tonale. Dopo la guerra partecipò all'impresa di Fiume con l'amico Giannantonio Manci.

Dopo l'avvento del fascismo collaborò con La Voce Repubblicana e con L'Italia libera, fondata da Randolfo Pacciardi. Alcuni giornali fascisti riportarono la notizia che il giovane Battisti avesse preso parte alla Marcia su Roma e per questo di essere stato conseguentemente ricompensato. Dimostrò che non era vero e sfidò a duello un giornalista napoletano che gli aveva dato del «figlio degenere». L'altro accettò, e Battisti rimase ferito ad un braccio.

Nel 1924 si laureò in scienze economiche. Tornato a Trento, creò una piccola azienda assieme a Giannantonio Manci. Insieme a Manci, Bacchi e Parolari fondò a Trento un gruppo di Italia libera. Nel 1930 si spostò a Milano e si unì a Giustizia e Libertà, poi nel 1942 al Partito d'Azione. Formò un gruppo di guide alpine con le quali aiutava a far fuggire dall'Italia persone ricercate, rimanendo in un'occasione gravemente ferito a entrambe le mani.

Il 10 settembre 1943, dopo l'annuncio dell'armistizio di Cassibile, Battisti passò in Svizzera ed entrò nel CLN di Lugano. Collaboratore dell'Office of Strategic Services americano, combatté nelle formazioni partigiane dell'Ossola alla vigilia della liberazione della zona e collaborò poi con la Giunta provvisoria di governo della Repubblica partigiana dell'Ossola. Da questa, ricevette il mandato di trattare con le autorità svizzere, con il CLN di Lugano e con la Legazione italiana di Berna, per i rifornimenti alimentari e lo scambio di altri prodotti con la vicina Repubblica elvetica. Operò con le formazioni partigiane della Valtellina e prese parte al Movimento di Unità Proletaria, poi confluito nel Partito Socialista Italiano di Unità Proletaria (che più tardi cambierà nome in PSI).

L'8 maggio 1945, dopo la liberazione, fu nominato sindaco di Trento dal CLN provinciale. I problemi principali erano legati alla carenza di case, distrutte dai bombardamenti, e di cibo. Alle elezioni del 2 giugno 1946 fu eletto all'Assemblea Costituente, dove diventò Segretario di presidenza. Di conseguenza si dimise dalla carica di sindaco. Morì il 14 dicembre dello stesso anno a Sessa Aurunca, in provincia di Caserta, in un incidente ferroviario. Assieme a lui persero la vita altre quattro persone e vi furono cinquanta-sessanta feriti. Alla Costituente fu sostituito da Danilo Paris.

Per ricordare Gigino Battisti è stato istituito in Trentino un Trofeo di ciclismo juniores.

Note

Voci correlate
Cesare Battisti
Ernesta Bittanti Battisti
Giannantonio Manci
Resistenza italiana
Repubblica partigiana dell'Ossola
Sindaci di Trento

Altri progetti

Collegamenti esterni

Figli d'arte
Deputati dell'Assemblea Costituente (Italia)
Sindaci di Trento
Militari italiani della prima guerra mondiale
Ufficiali del Regio Esercito
Persone legate agli alpini
Brigate Giustizia e Libertà
Persone legate alla Resistenza italiana
Antifascisti italiani
Legionari fiumani
Morti per incidente ferroviario
Irredentismo italiano

redpajama_set_name: RedPajamaWikipedia


 Services: Advanced Therapeutics Prof Massage and Bodywork for pain relief & relaxation, Roselle IL.
We offer focused therapeutic massage using one or more of the advanced techniques listed below. Great for treatment of injury, pain relief, chronic pain management, post workout recovery, or with the goal of achieving structural change within the body. You can also choose a relaxation focus for an enjoyable, relaxing treatment intended to help you relax and relieve stress without additional focus on underliying/chronic issues. Or try our favorite--a mix of both! Your session is tailored personally for you, every time!
Ortho-Bionomy® Positional Release is a non-invasive form of therapy which is highly effective in helping alleviate both acute and chronic pain and stress patterns. Gentle movements and positions are used to facilitate change within the body at a very deep level. A strong focus is placed on the comfort of the individual; no forceful movements are used. This technique may be performed with the client fully clothed.
Myofascial Release is a safe and very effective hands-on technique that involves applying gentle sustained pressure deep into the Myofascial connective tissue restrictions to eliminate pain, restore motion and elongate fascia (which surrounds every muscle on a cellular level).
Note: you may wear loose shorts and t-shirt/sports bra.
Traditional Thai Bodywork, also called Thai Yoga Therapy, is a therapeutic technique that dates back thousands of years. It is a deep, full-body treatment, performed on a mat on the floor, which includes both stretching of the joints and muscles, and compression applied by various means to the ten major energy channels, or sen lines. The result is an opening and energizing of the entire body to create balance and healing. Note: wear loose, comfortable clothing.
Lymphatics is a safe, gentle and effective way to unlock, balance and normalize lymph flow, improve endocrine function and health, and relieve pain and discomfort. Working with reflex points allows us deep within the body to relieve congestion, while smooth, soothing strokes are also used to further increase circulation and flow. Lymphatic congestion is often at the root of pain, poor organ function, endocrine system imbalance and pelvic imbalance. This technique may be performed with the client fully clothed.
Couples Massage Experience is a one-of-a-kind 75 minute massage experience where we open the doors between our treatment rooms to expand the space, creating a unique environment where you and your guest can enjoy your massages together. Also included is Sensation blend aromatherapy, fresh roses, chocolates & a refreshing beverage. *Be sure to book this service in the same time slot with a separate therapist for each person.
A mini version of our Couples Massage Experience. A 45 minute massage starting with the neck and hands using our Relaxing Therapeutic Massage Creme (containing certified organic botanicals to reduce tension, ease stress and promote relaxation) followed with by the ultimate foot massage using our Marine Therapy Pedi-Balm (with healing ingredients that rejuvenate, stimulate circulation, soften and soothe your feet leaving a powdery non-slip finish).
We convert our two treatment rooms into one so you and your loved one can enjoy this 45 minute getaway together! *Be sure to book this service in the same time slot with a separate therapist for each person.
We also offer: Corporate Outcall & Chair Massage. Call for details.


I have seen several renditions of this recipe on various blogs such as Not The Normal Teenage Fare and Chocolate-Covered Katie and I originally passed it up because I thought there was no way, it was too good to be true. Out of part curiosity, part sheer boredom and an intense sweet tooth I decided, why not give it a try. Now when I tried it at first I didn't like it but after refrigerating it overnight, it was unreal. I even had my coworker try it just to make sure my taste buds were not deceiving me. Yes friends, this is a healthy recipe for "cookie dough".
1. Throw it all in a food processor and mix until smooth. Dumb in your chockie chips stir and toss it in the fridge overnight. Wake up to an unbelievably tasty treat that you can literally eat by the spoonful and not feel (that) guilty. Glorious I tell you, just glorious.
I apologize in advance for this but we had a little doggie photo shoot last night before we went to bed and since I am totally obsessed with my babies, I just had to share these with you….
Look at my Mr. Big manning his post….on my pillow! He sleeps above my head every night, it's hilarious! That is until Lola comes and steels his spot….
This entry was posted in Recipes and tagged cookie dough dip, diet, diet desserts, health, healthy cookie dough, healthy dessert, healthy dessert recipe, nutrition. Bookmark the permalink.
I love cookie dough recipes! I have tried a version with chickpeas and you would never guess they were in the dough…I will have to give your recipe a try!
Yum yum yum!! I LOVE cookie dough and cookie dough "substitutes" because I wouldn't want to eat it raw!
I bought a jar of chick peas just for this purpose and still haven't made it but I am pretty sure it had=s to be good because I have seen a zillion people who doubted but then loved it!
I love chickpeas in desserts 🙂 I've made something similar and absolutely loved it!
I'm so intrigued! Will be trying this soon!
I LOVE cookie dough dip! You're right, straight from the food processor it still tastes rather beany and meh but once you give it time to mingle and chill the flavors are unreal! My favorite dipper is pretzels but honestly I'd rather eat it straight up!
PS- your dogs are absolutely ADORABLE!
I need to go out and get all of these ingredients, as this recipe looks great. Thanks for sharing this on The Healthy Hop!


text:
import flatbuffers

class UIHardwareState(object):
    __slots__ = ['_tab']

    @classmethod
    def GetRootAsUIHardwareState(cls, buf, offset):
        n = flatbuffers.encode.Get(flatbuffers.packer.uoffset, buf, offset)
        x = UIHardwareState()
        x.Init(buf, n + offset)
        return x

    # UIHardwareState
    def Init(self, buf, pos):
        self._tab = flatbuffers.table.Table(buf, pos)

    # UIHardwareState
    def GpuMemory(self, j):
        o = flatbuffers.number_types.UOffsetTFlags.py_type(self._tab.Offset(4))
        if o != 0:
            a = self._tab.Vector(o)
            return self._tab.Get(flatbuffers.number_types.Int64Flags, a + flatbuffers.number_types.UOffsetTFlags.py_type(j * 8))
        return 0

    # UIHardwareState
    def GpuMemoryAsNumpy(self):
        o = flatbuffers.number_types.UOffsetTFlags.py_type(self._tab.Offset(4))
        if o != 0:
            return self._tab.GetVectorAsNumpy(flatbuffers.number_types.Int64Flags, o)
        return 0

    # UIHardwareState
    def GpuMemoryLength(self):
        o = flatbuffers.number_types.UOffsetTFlags.py_type(self._tab.Offset(4))
        if o != 0:
            return self._tab.VectorLen(o)
        return 0

    # UIHardwareState
    def HostMemory(self):
        o = flatbuffers.number_types.UOffsetTFlags.py_type(self._tab.Offset(6))
        if o != 0:
            return self._tab.Get(flatbuffers.number_types.Int64Flags, o + self._tab.Pos)
        return 0

def UIHardwareStateStart(builder): builder.StartObject(2)
def UIHardwareStateAddGpuMemory(builder, gpuMemory): builder.PrependUOffsetTRelativeSlot(0, flatbuffers.number_types.UOffsetTFlags.py_type(gpuMemory), 0)
def UIHardwareStateStartGpuMemoryVector(builder, numElems): return builder.StartVector(8, numElems, 8)
def UIHardwareStateAddHostMemory(builder, hostMemory): builder.PrependInt64Slot(1, hostMemory, 0)
def UIHardwareStateEnd(builder): return builder.EndObject()

redpajama_set_name: RedPajamaGithub


Wossner Pistons high performance forged pistons develop the superior power for convincing success of famous teams at national or international racing events. As innovative specialists, we try to improve our products daily to provide our customer only the best. Therefore we fall back on the newest technology in all parts of the company. Permanent quality management guarantees the high quality of Wossner Pistons products and consequently the satisfaction of our customers. Made in Germany.


Outstanding job this past Friday at the Pep Rally and our first Home Football Game vs. Cerritos! The band and color guard looked and sounded great at our first public performance! Thank you to all the parents who came to support the students and helped with concessions and equipment!
This week we have: An Away Football Game at Artesia High School! On Saturday we have an e-Waste Fundraiser and an important rehearsal where we'll be learning new material for next Friday's Home Game.
The 2nd Donation of $125 is due tomorrow, Monday, September 14th in the Drop Box. Checks are made payable to "Gahr Band Boosters." We also accept major credit cards. We cannot pay our instructional staff or for field show competitions without your donation.
Join us this Wednesday, September 16th for a Field Tournament Meeting at Coco's (11510 South St, Cerritos, CA 90703). All parents are welcome and we need your help to make this a successful event and fundraiser!
The Gahr High School Band & Color Guard are having an eWaste Recycling Drive THIS SATURDAY, September 19th from 8AM to 1PM! Drop off is in the main parking lot by the Child Development Center. Clear out your garage and bring your used computers, monitors, TVs, microwaves, wires, and electronic junk.
WINDS: If you have not passed all of your memorization tests for this past week, it is your responsibility to make these up so you can perform with the group. The last day to make up the Star-Spangled Banner, Fight Song, and Mvt. 4 - Parts 1 & 2 is next Wednesday, September 23rd.
Great work and improvement this past week! We will continue sight-reading new tunes this week. Please arrive 10-15 minutes early to set up and warm up so we can start on time!
AFTER SCHOOL: Make Up Memorization Tests. DEADLINE IS WEDNESDAY 9/23/15.
On Friday, the entire Gahr Marching Gladiators will be bussing to the Artesia away football game to cheer, play pep tunes, and support our team!! Wear your field show t-shirt and jeans.
6:30PM Start playing pep tunes!
HALF-TIME: We will have a meet & greet with the Artesia band! Remember you are representing Gahr High School at all times and always be respectful.
3RD QUARTER: We will have a break where you can use the restroom and get food from concessions (bring your own money).
Hydrate and go to bed when you get home!
8:00AM-1:00PM eWaste Recycling Drive! Clear out and donate all your unwanted electronic junk!
Hydrate, eat breakfast, wear athletic clothes/shoes, hat, and bring 1-gal water jug & money for lunch.


As your local Farmers® agent in Fresno, CA, I help customers like you identify the insurance coverage that best fits your needs. This process is straightforward and personalized to help make you smarter about insurance. I have the knowledge and experience to help you better understand your coverage options--whether that's auto, home, renters, boat & motorcycle, business insurance and more.
Give me a call at (559) 455-1197 and I'll be happy to answer any questions you might have.


text:
A Wrinkle in Time (PG)
Reviewed by Joel Bourgeois on March 10, 2018
I have not read Madeleine L'Engle's A Wrinkle in Time, which is a shame, as I imagine it is a much better work than Ava DuVernay's film by the same name. Of course, "See Spot Run" would also be a better work than Disney's latest live-action effort, which manages to be so devoid of merit, personality, and plot that it will be hard to write much about it (other than hurling insults at it, which I have already failed at refraining from). The thing that is truly saddening, however, is that the film has a glimmer not just of interesting thematic exploration, but of virtue and righteousness, which I am certain is only present because it is weaved so intimately within the source material that the director and screenwriters' inability (or perhaps unwillingness) to comprehend them could not snuff them out entirely.
What I find most interesting about DuVernay's A Wrinkle in Time is that it has the exact opposite problem of the last film I reviewed, The Shape of Water. In Del Toro's film, the craft is excellent, but at its heart lies a perversion of goodness. DuVernay's probably has a heart as pure as gold, it is just impossible to tell because it was made so poorly. This just turns out to be two sides of the same coin, and A Wrinkle in Time ends up being just as much a waste of time and labor as Shape of Water – two films that are actively bad, but really earnest in believing what they are doing is good.
The film begins by attempting to show a strong father-daughter relationship between a young Meg (Storm Reid) and her dad, Dr. Alex Murray (Chris Pine) through their mutual scientific interests in her father's at-home physics lab (which looks nothing like an actual physics lab). Jump to four years later and her father has disappeared, leaving Meg, her mother, and adopted brother Charles Wallace (Deric McCabe) in despair. For Meg this translates to a terrible middle school life (her grades have been steadily declining and she always appears exhausted). She is teased by the other girls, but luckily catches the eye of a popular boy, Calvin O'Keefe (Levi Miller). One night her family is visited by a strange woman, Mrs. Whatsit (Reese Witherspoon), who seems to know all of them. The next day, Meg, Calvin, and Charles are hanging out in their backyard when three women appear out of thin air: Mrs. Whatsit, Mrs. Who (Mindy Kaling), and Mrs. Which (Oprah Winfrey). They learn that Dr. Murray had figured out how to "tesser," the verb form of "tesseract" (yes, just like from those other scientifically illiterate Disney-owned films) across the galaxy using only his mind. The Mrs.'s tesser with the three kids to a distant planet that looks a lot like Earth with the saturation turned up. Dr. Murray is obviously not there, but they learn the direction he headed. They then tesser to a rather drab planet where they meet Happy Medium (Zach Galifianakis) who helps Meg discover where her father is: the It, an evilness that is spreading across the universe, similar to Dormammu in Doctor Strange.
I should warn you, this synopsis makes the film sound a lot more interesting than it actually is. There are certainly some interesting ideas running in the background of this film, particularly in these metaphysical-turned-physical entities that drive the plot (the three Mrs's and the It), but the film itself spends no time with them. It is briefly explained that the It is what turns people against each other, and the film cuts to scenes of Meg getting teased at school or Calvin's father reprimanding him for his mediocre grades, but this is never felt. The It offers no sense of fear or danger, but the Mrs's are portrayed with even less finesse, acting as nothing more than a method of exposition and transportation. I learned from Steven Greydanus' review that the three Mrs.'s are supposed to be a representation of the Holy Trinity, but you would not know it from watching the film. In fact, Mrs. Which states that they are "part of the universe," clearly undercutting the spirituality of these characters and, by-and-large, of the film.
Beyond the muddy thematic problems of the film, it still does not succeed. There is no sense of tone. This is not entirely true, as the beginning of the film is at least functional in this respect, with bullying and unrest being something DuVernay had already portrayed with much greater success in Selma, but it is as the film moves towards fantasy – the main reason the audience is there – that things fall apart. We are treated to a rather colorful world, nothing special, but it is passable. The script is filled with some choice lines: "We need warriors who can fight the It," Mrs. Which tells Meg. Then there's the cinematography. Shots are framed strangely, there seems to be no understanding of camera movement, and it all adds up to a visual nothingness that the It would be proud of. But the worst offender is the soundtrack, or rather the choice to insert random pop songs into scenes for no rhyme or reason. If George Lucas' American Graffiti is a masterclass on how to use popular music to tell a story, then this film is a class on how to use it to ruin one.
The end result is a science fantasy with very little understanding of actual science (e.g. quantum entanglement can be described as two particles "in love" or that entanglement can be replicated above the quantum level so as to translate to teleporting with your mind) and no sense of fantasy (e.g. when Mrs. Whatsit transforms into a giant green flying creature and the kids ride on her back, Meg's response is to poorly describe the fluid dynamics that cause the phenomenon of lift instead of being in awe of the sublimity of the moment). It is fantastical when it should be scientific and scientific when it should be fantastical.
Near the very end of the film, Meg is attempting to save Charles Wallace from the It, which has taken over his mind. The line she saves him with is: "And you love me, because I deserve your love" (emphasis mine). This is a perfect lens through which all the problems of the film can be seen, a trite line reflecting failings both tangible (dialogue, soundtrack, cinematography, acting, direction, etc.) and philosophical. It misunderstands its source material, which in this case means misunderstanding what love is entirely, being seen as something that is deserved and not something that is given to others without condition. It's Interstellar for kids, if it were directed by Christopher Nolan after being hit on the head with a polo ball.
Joel Bourgeois
Joel Bourgeois graduated from Biola University with a degree in Physical Science. He also attended the Torrey Honors Institute, where he developed a love for reading (or watching), writing, and discussing the Good, the True, and the Beautiful. Other than film, Joel's main interests include amusement parks and automobiles, his favorites of which are Cedar Point and the McLaren F1, respectively.
One Response to A Wrinkle in Time
Keith Buhler said on	 March 27, 2018 at 11:39 am
Ouch. Thanks for the scathing review. I had heard some negative things, but you've convinced me that I would not enjoy the film. Truth hurts, but it's true. Cheers!
Notice: It seems you have Javascript disabled in your Browser. In order to submit a comment to this post, please write this code along with your comment: 630b8e6c4ec8ce8cf069dc15d0f7b604
Fantasy, Science Fiction, Terrible
Chris Pine, Deric McCabe, Levi Miller, Mindy Kaling, oprah winfrey, Reese Witherspoon, Storm Reid, Zach Galifianakis

redpajama_set_name: RedPajamaCommonCrawl


Surrey RCMP responded to a stabbing on Christmas morning.
A man is in hospital being treated for serious injuries after he was stabbed at a home in Newton.
At about 3 a.m. Sunday (Dec. 25) a number of individuals knocked on the door of a home in the 7400-block Todd Crescent.
An altercation broke out and a man was stabbed.
He was taken to hospital where he is being treated for serious, but not life-threatening injuries.


When you run a business, there are new opportunities available in the credit world that a regular person cannot get. You should take advantage of these perks and use them to better your bottom line.
Many credit card companies offer discounts to businesses to use their business credit cards at certain locations. For you, this could mean a 10 percent savings at the office supply store you frequent. When you are looking at which business credit cards to sign up for, look for any partnership programs. If you can find a card linked with a store you use regularly, this could mean major savings.
Many of today's credit card companies offer reward programs. It could be cash back, airline miles, or any of a number of other perks. For business use, these rewards could add up quickly. If you can, put as many expenses as possible on the card to rack up points. Just make sure to pay off the card, as you would have other bills, at the end of the month. That means no interest charged, but many reward points put in your name.
Using a business credit card for the majority of your business purchases will give you the added bonus of having everyone on one receipt at the end of the month. Instead of going through a stack of bills and payment forms, you can have a line-by-line list of where the money has gone.
Since most businesses are seen as a much safer risk than an individual is, most business credit cards have a much lower interest rate than personal credit cards offer. While you should try to pay off your credit cards every month, if you do need to purchase large capital items for the company, you can take comfort in the fact the interest will not be piling up as quickly.
If you are in a field where you must trust your employees with expense accounts, look for a credit card company that offers employee credit cards. By giving each of the employees their own company credit card, you can set limits, to keep their spending in check, and also be able to easily keep up with just where that money is going when the monthly statement arrives.
Business credit cards are not just an easier way to pay, but also can be a very rewarding way to give your company a little more bang for it's buck, while also keeping a better watch on where those bucks are going.


For a limited time, get a $150 prepaid card when you sign up for DISH!
For the very best in TV viewing, no one does it better than DISH Network. With the top satellite TV service in the country you get the choice you want in your TV lineup regardless of where you live, as well as cutting edge technology you will appreciate. Plus DISH is affordable; you can even get DISH Network packages, including the coveted Hopper®, for under $2 per day.* Only DISH gives you everything you want in a satellite TV service, even those things you didn't know you wanted. For so many reasons, DISH is the best TV solution for you. Check out its impressive offerings.
Your local channels are always complimentary with DISH Network. Your subscription automatically includes those channels in your area, so you never have to pay a dime for local programming.
Quality picture image for your TV viewing pleasure is yours with HD TV. With more HD channels than any other provider, you get the impressive clarity that only HD programming delivers. Only DISH Network gives you over 200 FREE HD channels for 24 months, with qualifying packages.
In order to ensure that your satellite DISH is installed and service set-up optimally, so you get crystal clear picture, DISH always has a certified technician handle your entire installation of up to 6 rooms, absolutely FREE. You can even get FREE rush installation so you get your service within as little as 24 hours.
The Hopper™ is the most technologically superior HD DVR available today. You get the luxury of being able to record up to 6 TV shows at once during primetime, so you never again have to miss a thing. With the Hopper, you get seamless playback options because you can skip the commercials. The DISH Network Hopper has the largest storage capacity of any HD-DVR, with the ability to store as much as 2000 hours of TV time.
High speed satellite Internet service from Qprism is available to you, regardless of where you live. It brings you speeds of up to 10Mbps, so you can do practically everything you want to do online quickly and easily, from the convenience of home. Generous data plans as high as 30GB of data are perfect, even for heavy users. With bundle pricing, you save on Qprism and DISH Network services when you get both.


This is everything a ham should be, sticky, sweet, juicy and tender. The freshness from the salsa cuts through the sweetness and keeps the pineapple theme running throughout the whole dish. We are lucky as we have an excellent butcher and we ordered 2 smoked gammons and were not disappointed. Sometimes old school joints taste just as good as the more expensive, all you need is time. This would also be delicious served cold, we ate ours warm with some new potatoes which went really well with the fresh zesty salsa. Our recipe was based on a recipe from delicious magazine.
Fill a large pan or stockpot with cold water, add the gammon and set over a high heat. Bring to the boil, then drain and rinse off the gammon (this removes some of the saltiness).
Rinse the pan out, then return the gammon to it. Add 500ml of the pineapple juice, then top up with water to cover the gammon completely. Add 2 of the star anise, then put the pan back over a high heat. Bring to a gentle simmer, then cook for 2 hours. Remove the ham and place onto a board and leave until cool enough to handle.
Meanwhile, put the remaining pineapple juice and star anise in a heavy-based pan with the sugar. Heat gently to melt the sugar, then bring the liquid up to a rapid boil and reduce for 15-20 minutes to form a thick, sticky glaze. Transfer to a bowl. Heat the oven to 220°C/200°C fan/gas 7.
Use a sharp knife to peel the skin off the ham, leaving on as much of the fat as possible. Score the fat diagonally in two directions to create diamond shapes, then thickly brush over the glaze. Reserve any leftover glaze for drizzling over.
Line a roasting tin with 2 layers of foil, then add the ham. Roast for 20-30 minutes, basting occasionally with the glaze, until the top of the ham is just beginning to char.
Drain off most of the liquid from the salsa, then toss through the herbs and chopped chilli. Thickly slice the ham and serve with the salsa and boiled new potatoes.


text:
Dr.Brock Lectures
Dr. Brock Talks
Meet Dr.Brock
Contact For Speaking Engagements
Meet Dr. Brock
Dr. Brandon Brock
DNP, DC, FNP-C, MSN, BSN, APRN, DACNB, DCBCN, BCIM, FICC
Ph.D Student: Texas Woman's University
Doctorate in Nursing Practice: Duke University
Doctorate in Chiropractic: Parker University
Advanced Practice Registered Nurse: Texas
Family Nurse Practitioner: Samford University
Orthopedic Nurse Practitioner: Duke University
Masters in Science: Nursing Practice
Bachelor of Science in Nursing: Hardin Simmons University
Bachelor of Science in Anatomy: Parker University
Global Clinical Research Scholar: Harvard Medical School
Stem Cell and Regenerative Medicine Fellowship Training: A4M
Dr. Brandon Brock is a clinician in Dallas Texas who holds a Doctorate in Family Nursing Practice from Duke University and is currently doing Ph.D. studies. He has also completed a specialization in orthopedics From Duke University and also has specialized fellowship training in regenerative medicine.
Dr. Brock also holds a Doctorate in Chiropractic and an undergraduate degree in anatomy and nursing science. He holds Diplomate status in Functional Neurology (ACNB) and nutrition (CBCN). Dr. Brock is also a Global Clinical Research Scholar from Harvard Medical School with interests in secondary analysis, survey design and clinical trials.
In Dallas Texas, he serves as a clinician at Carpathia Collaborative. He enjoys teaching and providing educational support to facilitate learning for multiple groups and agencies. This includes topics that ranges from nutrition, neurology, orthopedics and regenerative medicine to pharmacology and governmental policy. His academic teaching and scientific contributions in Xymogen, Functional Medicine Meetings, Vibrant America, Dr. Brock Lectures, Erchonia, Functional Neurology Seminars, BTB Health Systems, Brainchat and SNA technologies. Dr. Brock is an adjunct faculty member for Maryland University of Integrative Health and National University of Health Sciences.
Dr. Brock received the most outstanding functional neurology teacher of the year from the ACA council of Neurology four years straight and two times from IAFNR (International Association of Functional Neurology and Rehabilitation). He also received the humanitarian award from IAFNR. Dr. Brock and is also the honorable recipient of the prestigious Living Legacy Award from Samford Universities Ida Moffett School Nursing in 2015 along with the award for most outstanding Functional Neurologist in 2020 from the International Association of Top Professionals (IAOTP). He has also been the spotlight student at Duke University.
His unique blend of clinical and academic experience along with a background in medicine, chiropractic, neurology, orthopedics, regenerative medicine, and nutrition has created an integrated clinical background that has helped him treat difficult cases and offers comprehensive angles on treatment, education, and clinical management.
He enjoys spending time with his wife, Tara, and his children, Addy, Zoey, Conner, and Kennedy.
Sign Up to stay up to date on the latest news & events for Dr. Brock
© 2023 · Dr. Brock Lectures · Built by Soaring Lotus Media


text:
Skarf (hangul: 스카프) var en sydkoreansk tjejgrupp bildad år 2012 av Alpha Entertainment.

Gruppen bestod av medlemmar även från andra länder, främst Singapore, och har varit inaktiv sedan 2014.

Karriär

Bakgrund
Skarf bestod vid debuten av de fyra originalmedlemmarna Tasha, Jenny, Sol och Ferlyn, varav Tasha var gruppens ledare.

Gruppnamnet kommer ursprungligen från det engelska ordet "Scarf", fast i Skarf står bokstaven "S" för Singapore och "K" för Korea, de två länder som gruppens medlemmar kom från. Skarf var också den allra första idolgruppen blandad med medlemmar från Sydkorea och Singapore. De utländska medlemmarna Tasha och Ferlyn hade redan ett intresse för koreansk kultur och kunde tala flytande koreanska trots endast ett år i landet vid debuten.

Debut med "Oh! Dance"

Den 9 augusti 2012 släpptes den första teasern från musikvideon tillhörande den nya tjejgruppen Skarfs debutsingel "Oh! Dance", producerad av duon Honeydew'o. Den 10 augusti 2012 släpptes individuella teaservideor för att introducera varje gruppmedlem, och den 11 augusti sändes det första avsnittet av reality-programmet Oh My SKARF på TV-kanalen MBC Music. Serien som följer gruppen inför sin debut pågick i totalt fem avsnitt.

Efter ytterligare en teaser från gruppens första musikvideo den 13 augusti, släpptes till slut debutsingeln "Oh! Dance" den 14 augusti tillsammans med hela den tillhörande musikvideon. På gruppens självbetitlade singelalbum Skarf inkluderades förutom debutsingeln även en låt med titeln "My Love", skriven av personerna bakom sångerskan Ailees hitlåt "Heaven". Samma dag presenterades också gruppen för första gången live vid ett evenemang som hölls för media i Seoul, där Skarf fick framträda med både "Oh! Dance" och "My Love".

Gruppen började under kommande veckor marknadsföra sin singel i musikprogram som Music Bank på KBS, M! Countdown på Mnet, och Show! Music Core på MBC. Den 18 och 19 augusti marknadsförde sig gruppmedlemmarna själva genom att personligen dela ut solfjädrar med gruppens bilder på i städer som Daejeon, Daegu, Busan och Gwangju, något som väckte uppmärksamhet då det är ovanligt för idolgrupper att göra. Efter marknadsföringen av "Oh! Dance" fokuserade gruppen även på att försöka marknadsföra sin andra låt "My Love" ytterligare. I oktober 2012 var gruppens ledare Tasha även med i en reklamfilm för mobilföretaget Pantech.

Medlemsförändringar, Luv Virus och inaktivitet
I slutet av december 2012 rapporterades det att Skarf genomgått förändringar och nu bestod av fem medlemmar istället för fyra, detta efter att Sol lämnat gruppen av personliga skäl och de två nya medlemmarna JooA och Hana anslutit sig till kvarvarande Tasha, Jenny och Ferlyn. I januari 2013 gjorde Skarf reklam i Singapore för Samsungs Samsung Galaxy Camera från produktfamiljen Samsung Galaxy.

Den 28 maj 2013 släpptes individuella videoteasers inför gruppens återkomst med singeln "Luv Virus", samt deras allra första album med samma titel. Den 31 maj 2013 släpptes musikvideon till singeln "Luv Virus", samt albumet Luv Virus som innehåller totalt fem låtar.

Sedan 2014 har gruppen varit inaktiv. Ferlyn lämnade först gruppen och påbörjade en solokarriär, vilket ledde till att fyra medlemmar återstod senast de var aktiva. Gruppen är däremot inte officiellt upplöst. I juni 2014 deltog gruppmedlemmen Tasha i den andra säsongen av TV-programmet Dancing 9 på Mnet.

Medlemmar

Diskografi

Album

Singlar

Källor

Externa länkar
Artistinformation och diskografi på MelOn

Sydkoreanska musikgrupper
Musikgrupper bildade 2012
WP:Projekt Korea


When I was in art school, there was a professor who taught a photo class that I believe was called Start to Finish. The point of the class was to start with an idea and see it through to completion, no matter how difficult things got. You had to find a way to make work out of what you had to work with. While I never took the class, the idea stuck with me. And now, in "real working life," I see how valuable this concept is. Basically all of my assignments are start to finish. So, with that in mind, I've begun a new photo documentary—a long term exploration. We will see what things shape up to be over the next year, no matter what obstacles may happen along the way.
Like everyone else in the retail side of the photo world, I just spent the last few days at the PhotoPlus Expo at the Javits Center here in New York. It was big, busy, and a great time to reconnect with old and new contacts in the industry. In fact, I nearly lost my voice from talking to so many people. Since I became a technical writer--more than a decade ago now--this has always been the one event I make time for no matter what.
The tech is cool, and essential to keep up on, but for me, the show is more about getting out there and showing my peers that I appreciate what they do, and that I appreciate them. In a world where it's so easy to communicate entirely by email, I value those face to face interactions. The photo industry is a really exciting place, filled with a lot of great people. Why wouldn't I want to go?
Anyone who writes for a living knows what The Visual Thesaurus is--it's that magical wonderland of words, glorious words. Whenever I feel that I've used an adjective, or any other word for that matter, too many times I plunk it into the good of VT, and instantly a beautiful interactive map of alternatives appears on my screen. I suppose I could use a paper thesaurus, but it wouldn't be quite so satisfying (I'll admit that sometimes I still do use one), nor would it produce so many options on demand.
I've used the site for years as a professional tool, and I'll be a diehard member for life (can I get a discount for that?). I had to renew my membership today, and it reminded just how much I love the site. It's how I keep my writing fresh, while at the same time expanding my vocabulary. Subscriptions are reasonably priced, especially when you consider the value you're getting. If you have never used it, go and check it out right now! I can't be responsible if you fall down a rabbit hole of word searches, however.
Friends like to ask me how (or why) I became a technical writer. And that's a valid question. When I was in college I remember seeing a technical writing course in the offerings, and wondering who would want to do that. It sounded so boring. As the fates would have it, my first job out of college...Jr. Technical Writer.
I quickly learned that the job was dynamic; it was more like working in a daily newsroom, in fact. Far more exciting than anything I had imagined. I also learned what other technical writers already knew: it was a good way to make a living, especially during the great recession. Where my friends were struggling to find freelance gigs photo assisting, I was working every day.
So the how. If you've read my bio you know that I went to school for photography and writing. I had written little stories and poems since I was old enough to form words on paper, and part of me always knew that I would be a writer. Yet, in school I felt photography would come first and the writing would support that work. What I hadn't quite appreciated was that I was becoming an expert in a niche technical field that I could also write about. That field was photography.
I was hired at B&H Photo right after graduation to write for their growing website. It turned out that I had the perfect combination of skills. Over the next eight plus years my knowledge of the photo world grew, as did my writing and editing chops. I moved up in the Web Department and held multiple publishing positions--each was an invaluable learning experience. Every day on the job was training in this thing called technical writing, including all its moving parts: research, contacting the people with the answers to my questions, keeping up on the industry, working with people, and of course, the actual writing and editing.
Now that I'm on my own I can see the benefits of this "training" even more clearly. I spent nearly a decade becoming the writer and editor I am today. While technical writing wasn't perhaps what I saw myself doing when I was in my early 20s, it turned out to be an awesome career that both kept me in the photo world and opened countless doors.
When I left my safe office job two years ago, I was excited and terrified at the same time. But I was ready. No matter which way I looked at it, I knew it was time to go out on my own. I haven't regretted it one bit. It hasn't always been easy, and being your own boss presents it own set of challenges, but it was definitely where my heart wanted me to be.
Leaving the world of cubicle-land was one of those moments when I just knew. Everything in me said "go!", and so I bent to the universe and did it.
Running my own business as a freelance writer and editor has come together for me in a somewhat beautiful way. All the pieces fit into place, the right people said yes, and the work began. Every day I learn more, and every day I feel grateful for having made this choice.
If you're on the fence about working for yourself as a writer, or otherwise, feel free to ask me your questions. I can't guarantee completely smooth sailing, but I can attest to the fact that if that's where you want to be, then it's worth it.
Thoughts about working for yourself, writing, art, and the photo industry.


ASCOM Calcium Carbonate Plant, El-Minya Industrial Zone, Egypt. ACCM's 20m calcium carbonate plant has a production capacity of 180000t per year.
calcium carbonate crushing germany grinding mill equipment. germany ballmills for grinding calcium carbonate Feb 15 2016 ZME heavy industry is the biggest stone .
calcium carbonate crushing germany grinding mill operation s m calcium carbonate plant has a production capacity oft perprovide German grinding technology .
calcium carbonate grinding german tech, Germany crusher . Nigeria calcium carbonate stone crushing equipment, mine .
calcium carbonat crushing station calcium carbonate crushing grading production line process chart Calcium Carbonate Crushing Germany process crusher .
Grinding Of Calcium Carbonate In Germany calcium carbonate crushing germany grinding mill is used in calcium Get More Info.
calcium carbonate crushing germany Crusher Machine calcium carbonate crushing germany european calcium carbonate pulvarizer crusher mill in germany .


This resource type allows you to link to any web page or other file on the public web. It also allows you to link to any web page or other file that you have uploaded into your course files area from your own desktop computer.
Normal web pages are simply displayed as they are, while multimedia files are dealt with more intelligently and may be embedded within a web page. For example, MP3 files will be displayed using a built-in streaming player, as will movie files, flash animations and so on.
There are many options for displaying your content in popup windows, framed windows and so on.
In particular, if your resource is a web application or other type of content able to accept parameters, you can choose to send information to your resource such as the user's name, their email, the course they are currently in, and so on.


text:
case project
AGNIESZKA KULESA
MAREK DĄBROWSKI
OSKAR CHMIEL
case project administrator:
MAREK PEDA
latest projects:
V4DevCo - V4 Development Cooperation Trialogue:...
V4 support to promote WB6 Common Regional Marke...
Equalising opportunities for the less developed...
INTERCEPT - Motivating Mobilizing Supporting Ne...
01 Dec 2021 - 31 Mar 2022
growth & trade, demography, labor & social policy
A new agenda for the Mediterranean: are the EU tools and means of action up to its ambitions?
In the context of the new Communication on the subject-matter presented jointly by the Commission and the EU's High Representative for Foreign and Security Policy (EEAS) in February 2021 the Committee on Foreign Relation of the European Parliament called for a study focused on the Mediterranean Sea.
The cooperation on the basin, to whom participate EU Member States and the non-EU Mediterranean coastal states, has a long history that begins with the Barcelona Declaration, continued in 2008 with the Euro-Mediterranean Partnership, and with the Global Strategy in 2016. This evolution brings to the 2021 "Renewed Partnership with the Southern Neighborhood: A new Agenda for the Mediterranean" set in the framework of the European Neighborhood Policy. The southern Mediterranean region is facing several challenges, from climate change to failure of states, and the European Union would like to cooperate with MENA partners to tackle the issue.
The main aim of this study is to provide a general overview of actions in the region, geopolitical considerations proposing policy recommendations for the EU toolbox. The study introduction will be structured with a summary of the evolution of the EU and Southern Neighborhood relations.
The main part of the study:
Assess the political, institutional and economic framework of EU towards Southern Neighborhood and evaluate the new policy's coherence with the objectives, principles and values contained in the EU's Treaties with the policy and legislative framework;
Analyse the key policy areas covered by the 2021 Commission communication;
Evaluate the communication strategy for the project along with EU's toolbox instruments and initiatives, and identify any missing elements;
Forecast potential scenarios for the future of EU-MENA relations.
The study will provide concrete recommendations to the EU and its partners, together with advises specifically for the European Parliament.
Project Leader: CASE- Center for Social and Economic Research (Poland)
Project Partner: IEMED
Project Client: European Parliament
V4DevCo - V4 Development Cooperation Trialogue: Reinforcing Sy...
STANISLAV BIELIEI
V4 support to promote WB6 Common Regional Market: one market f...
Equalising opportunities for the less developed regions of Arm...
INTERCEPT - Motivating Mobilizing Supporting Neets Green Caree...